tbuckley/cabot-search huggingface dataset:
Abstract P2086: Wirelessly Powered Miniaturized Intravascular Pacemaker Based On Inductive Coupling
Authors: Qingyu Cui, Parinaz Abiri, Susana Cavallero, Yu-Chong Tai, Tzung K Hsiai
Journal: Circulation Research (2022)

Introduction: Despite unparalleled advantages, clinical lead-associated complications of the conventional pacemakers remain to compromise patient safety and survival, accounting for nearly 10% of all implants. The leadless pacemakers from Medtronic or St. Jude Medical are revolutionary products, however, the integrated battery introduced new clinical constraints and health risks. Therefore, developing leadless pacemakers incorporating wireless powering owns special clinical significance to further the miniaturized integration and reduce the repetitive mechanical workload for the hearts. Methods and Results: Hereby, we achieved the leadless intravascular miniaturized pacemaker powered by electromagnetic inductive coupling. The miniaturized assembling was built up from flexible circuit boards, integrating with receiver coils and tiny electrical components for the RF-DC converting. The substrate circuit board will be bent into a cylinder with a diameter of 2.7 mm and filled with PDMS to achieve the electrical isolation and form a narrower tip for easy insertions (Figure 1a,b). The voltage of DC pulse converted at the wireless pacemaker depends on the DC voltage for the RF amplifier and the gap between the coils, ranging from 0.5V to 5V or higher (Figure 1c). After inserting the pacemaker into the anterior vein, the pacing demonstration showed the stimulation spikes and the following regular cardiac Q-R-S-T waves, indicating the pacemaker can stimulate the intrinsic cardiac rhythms (Figure 1d,e). Conclusions: The proposed medical device reveals the potentials of cardiac pacing from the anterior veins and paved the way to further device miniaturization for the intravascular deployment.
Clinical diagnosis of pneumococcal, adenoviral, mycoplasmal and mixed pneumonias in young men
Authors: K Lehtomaki
Journal: European Respiratory Journal (1988)

Clinical characteristics and course of disease of 19 pneumococcal, 11 adenoviral, 15 mycoplasmal and 10 mixed pneumonias, diagnosed in 55 military conscripts, were compared. Controls consisted of 104 conscripts with upper respiratory infections (URI). The triad: productive cough, blood stained sputum, and chest pain aggravated by breathing (pneumococcal score) distinguished pneumococcal and mixed pneumonias but not adenoviral and mycoplasmal pneumonias from URI. Higher C-reactive protein (CRP) and white blood cell (WBC) count distinguished the pneumococcal pneumonias, but not the other pneumonias, from URI. The pneumococcal scores and simple laboratory tests on admission were compared. The score effectively separated pneumococcal from adenoviral and mycoplasmal pneumonias, and patients with mixed infections from mycoplasmal infections. Higher CRP values and WBC counts distinguished pneumococcal pneumonia from other pneumonias. Auscultation revealed crackles in 27% of adenoviral and in 60-70% of mycoplasmal, pneumococcal and mixed pneumonias. Maxillary sinusitis was more common in pneumococcal (56%) than in mycoplasmal (7%) or mixed pneumonia (10%) or URI (14%). Pneumococcal pneumonias differed in most respects from the other groups. It is difficult to distinguish between adenoviral, mycoplasmal and mixed pneumonia and also URI.
Effect of different volumes of BAL fluid on arterial oxygen saturation
Authors: M Pirozynski, P Sliwinski, J Zielinski
Journal: European Respiratory Journal (1988)

We monitored arterial oxygen saturation (StcO2) continuously using the OHMEDA Biox 3700 oximeter. We studied seven patients undergoing a 100 ml bronchoalveolar lavage (BAL-100), seven patients undergoing a 200 ml bronchoalveolar lavage (BAL-200), and seven patients during diagnostic fibreoptic bronchoscopy alone. Immediately following insertion of the bronchoscope a brief increase in StcO2 level (0.3-0.5%) was seen, followed by a gradual decline, never exceeding 2-5% during the diagnostic bronchoscopy. Introduction of lavage fluid into a segmental bronchus always produced a further decline in StcO2. In the BAL-100 group the fall did not exceed 7%, whereas in the BAL-200 group a fall of up to 15% from the baseline level was observed. Return to initial values was seen in most of the patients within 10 min following completion of the procedure. Only in those patients with the most profound StcO2 fall was this period increased, up to 30 min.
alpha-Amylase in resectable lung cancer
Authors: P Lenler-Petersen, A Grove, A Brock, R Jelnes
Journal: European Respiratory Journal (1994)

Biochemical analysis and immunohistochemical techniques support the theory that hyperamylasaemia in lung cancer is due to amylase production in carcinoma cells. The vast majority of amylase-producing carcinomas are adenocarcinomas with amylase isoenzyme similar to the salivary type. This prospective study assesses alpha-amylase expression in resectable lung cancer. Seventy four patients with resectable lung cancer were studied. Amylase activity in tumour tissue was analysed and isoamylase identification performed. Immunohistochemical analysis was performed using a polyclonal rabbit antibody against human salivary amylase. Hyperamylasaemia occurred in 13 out of 70 patients. Increased amylase activity in tumour tissue was found in 10 out of 52 cases, of which only two were associated with hyperamylasaemia. With the exception of one large cell carcinoma and one squamous cell carcinoma, the tumours were adenocarcinomas. Immunohistochemical analysis revealed amylase expression in seven adenocarcinomas and two adenosquamous carcinomas. In conclusion, immunohistochemical amylase expression was restricted to carcinomas with adenomatous differentiation. Biochemical analysis confirmed amylase production in 5 of 7 cases examined, the tissue amylase isoenzymes being of salivary type. However, hyperamylasaemia and a slightly increased amylase activity in tumour tissue may be caused by factors other than amylase-producing carcinoma cells.
Abstract P3113: RAF 'Paradox Breaker' Inhibitor, PLX8394, Enhances Inflammation And Apoptosis In Murine Hypertension <i>In Vivo</i>
Authors: Susanna T Cooper, Giles O Malone, Zoe H Haines, Daniel N Meijles
Journal: Circulation Research (2022)

Introduction: The ERK1/2 cascade, activated by RAF kinases, is a key pathway for cardiac remodelling and cytoprotection. Due to activating oncogenic mutations in BRAF, small molecule RAF inhibitors have been developed. However, owing to inhibitor resistance or paradoxical ERK1/2 pathway activation, a new generation of ‘paradox breaking’ drugs are currently in clinical trials. Our previous work characterised RAF targeting in hypertension, where it is instrumental in driving cardiac remodelling. Here we explored whether use of the RAF paradox breakers (e.g. PLX8394) are viable modalities for targeting RAF in hypertension. Hypothesis: We hypothesize that RAF ‘paradox breakers’ will protect cardiac function by inhibiting maladaptive hypertensive remodelling. Methods &amp; Results: To assess the role of RAF inhibition in cardiac adaptation to hypertension in vivo , C57Bl/6J mice were treated with angiotensin-II (AngII; 0.8mg/kg/d, 7d n=8;) without/with 5mg/kg/d PLX8394 (n=11). PLX8394 alone had no detrimental effect on cardiac function or remodelling. AngII promoted cardiac hypertrophy, by increasing left ventricular (LV) wall thickness (WT) and decreasing LV internal diameter (ID; assessed by echocardiography). PLX8394 had no impact on AngII-induced hypertrophy (WT:ID, p=0.45), or abundance of AngII-induced hypertrophic Nppa (p=0.77) or Nppb (p=0.49) mRNAs. Additionally, PLX8394 did not affect AngII-induced perivascular fibrosis (p=0.69; picrosirius red histology) or moderate Col1a1 (p=0.22) and Col3a1 (p=0.82) mRNAs. However, PLX8394 use in AngII-hypertension was pro-inflammatory, with increased pro-inflammatory cytokines ( Il1b , p=0.02; Il6 , p=0.008) and the inflammatory cell marker CD45 (p=0.001) mRNAs; a response echoed in hearts labelled by immunohistochemistry for CD45 (p=0.02). Moreover, western blotting revealed elevated PARP cleavage (p=0.005), indicating increased apoptosis with PLX8394 use. Conclusion: Despite no adverse effect on cardiac function or global hypertensive remodelling at 7 days, RAF inhibition by PLX8394 appears to be pro-inflammatory and pro-apoptotic. Thus, long-term use of RAF ‘paradox breakers’ in hypertensive individuals may be cardiotoxic and promote adverse cardiac events.
Abstract P2031: Evaluation Of Adenosine Monophosphate-activated Protein Kinase Activator MK-8722 In Human Induced Pluripotent Stem Cell Derived Cardiomyocyte Monolayer And Microtissue (Biowire II) Models
Authors: John P Imredy, Holly Clouse, Armando Lagrutta, Michael P Graziano, Krista M Durney, Wilson Hsieh, Jamie Gearhart, Brian Schriver, Nathan W Bay, Nicole T Feric
Journal: Circulation Research (2022)

MK-8722, a systemic pan-AMPK activator improves glucose homeostasis in animal models of diabetes, but causes cardiac hypertrophy # . Two- and 3-dimensional tissue (2D,3D) constructs of human induced pluripotent stem cell derived cardiomyocytes (CM) (iCells, Fujifilm/CDI) were used to probe the translatability of cardiac hypertrophy and the role of AMPK in cardiomyocyte function. Chronic 10-day exposure (2 μM and 10 μM MK-8722) of iCell cardiomyocyte 2D monolayers, probed via monitoring of cellular impedance (CardioECR, Agilent), revealed a decrease in beat amplitude (-13%,2μM;-49%,10μM) as well as an increase in excitability, based on the ability to follow higher pacing frequencies (+81%,2uM;+34%,10uM). Direct force measurements in 3D iCell CM tissues (Biowire II, TARA Biosystems) reported loss of contractility when stimulated at 1Hz (-74%,2μM;-90%,10 μM), as well as changes in passive resting tension (+18%,2μM;-75%,10 μM) over chronic six-week exposure. MK-8722 caused a marked increase in Biowire excitability as revealed by a large drop in the voltage threshold of entrainment of paced tissues (-36%,2μM;-43%,10 μM). The increased excitability of both 2D and 3D CM models suggests a cellular correlate of the increased electrocardiographic QRS amplitude observed in rhesus monkeys upon chronic dosing with MK-8722 # . Hypertrophy of the Biowires could be clearly observed at the end of the 6-week incubation and presented as increased microtissue widths (+5%,2μM; +10%,10μM) and thickened regions of attachment to the chamber force sensors at each end of the Biowire. Volume estimation revealed increases (+22.3%, 2μM; +31.4%, 10 μM) in Biowire tissue volumes that were comparable to heart hypertrophic changes in preclinical test species # (mouse, rat, and rhesus monkey). The effect of 10μM MK-8722 was more pronounced when treatment began before tissues had completed a multi-week electrical stimulation maturation protocol, rather than after. The functional effects in both 2D and 3D CM models, and the contractile and structural readouts of the 3D Biowire model were highly informative in the interpretation of the clinical applicability of the pleiotropic cardiac effects of MK-8722 observed in preclinical testing. # Myers, et al. Science 357, p 507-511 (2017)
The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis
Authors: JM Ray, WG Stetler-Stevenson
Journal: European Respiratory Journal (1994)

One critical event of tumour invasion that signals the initiation of the metastatic cascade is thought to be interaction of the tumour cell with the basement membrane. Basement membranes may also pose as barriers to tumour cell invasion at multiple points later in the metastatic cascade, including during the processes of vascular infiltration and extravasation. Thus, an important proteolytic event in the metastatic cascade, and also angiogenesis, appears to be degradation of basement membrane components. A specific class of extracellular matrix degrading metalloenzymes, the matrix metalloproteases, and their endogenous inhibitors, the tissue inhibitors of metalloproteases, are thought to have a role in the creation of the proteolytic defect in basement membrane type IV collagen. We will review the evidence which indicates that matrix metalloproteases and tissue inhibitors of metalloproteases are essential for tumour cell invasion and angiogenesis. The regulation of matrix metalloproteases will be discussed, including gene activation and transcription, messenger ribonucleic acid (mRNA) stability, binding of proenzymes to cell membranes and/or matrix components, proenzyme activation, and inactivation by endogenous inhibitors. We will also discuss the mechanism for tissue inhibitor of metalloproteases-mediated inhibition of tumour invasion and angiogenesis. This appears, at least in part, to be through inhibition of protease activity required for cellular invasion, although recent observations suggest that tissue inhibitors of metalloproteases affect other distinct groups of biological activities through mechanisms other than matrix metalloprotease inhibition.
Abstract P3104: Extracellular Vesicles From The Infarcted Heart Facilitate Tumor Growth
Authors: Tal Caller, Olga Shaihov–Teper, Yeshai Schary, Daria Lendengolts, Itai Rotem, Racheli Peled, Ruty Shai, Uri Amit, Efrat Glick-Saar, Dan Dominissini, Alex Boomgarden, Crislyn D'Souza-Schorey, Nili Naftali-Shani, Jonathan Leor
Journal: Circulation Research (2022)

Background and Aim: Heart disease might be an independent risk factor for cancer (reverse cardio-oncology). The cellular and molecular mechanisms that link heart disease to cancer remain elusive, and specific therapies are limited. We hypothesized that cardiac extracellular vesicles (cEVs) secreted by diseased hearts carry and disseminate factors that promote tumor growth. Methods &amp; Results: We subjected female mice to myocardial infarction (MI) or sham-MI and 28 days of follow-up. Left ventricular remodeling was confirmed by echocardiography. To determine the role of cEVs in tumor growth, we focused on cardiac mesenchymal stromal cells (cMSCs), which play a central role in cardiac repair, remodeling, and fibrosis. Thus, we isolated cMSCs from mice hearts 10 or 28 days after MI or sham MI. cMSCs after MI secreted more small EVs than cMSCs from sham-MI. Proteomic analysis revealed a distinctive profile of cEVs after MI ( Fig A ). Purified cMSC-EVs targeted both breast and lung cancer cells in vitro. A scratch assay showed that MI-cEVs facilitated cancer cell proliferation and migration two times faster than sham-MI cEVs ( Fig B , p=0.0002). Finally, lung or breast cancer cells were inoculated into the hind limb or mammary pad 10 days before or after MI. Tumor growth was monitored by serial ultrasound examinations. While MI stimulated tumor growth, EV inhibition by GW4869 markedly attenuated this effect ( Fig C ). Conclusions: We show, for the first time, that cMSCs from the infarcted and remodeling heart secret EVs that target tumor cells and facilitate tumor growth. We propose cEVs as potential mediators and therapeutic targets in patients with concomitant heart disease and cancer.
Abstract P2073: Rbx2-CRL5 Mediates Mitochondrial Ubiquitination And Mitophagy To Maintain Myocardial Homeostasis Independent Of Parkin
Authors: Wenjuan Wang, Ermin Li, Jianqiu Zou, Chen Qu, Juan Ayala, Kayla Pratt, Jinbao Liu, Jie Li, Huabo Su
Journal: Circulation Research (2022)

The ubiquitin (Ub) ligase Parkin has been recognized as a central player in mitophagy. In contrast to its presumed importance in the heart, ablation of Parkin fails to impact homeostatic mitophagy and cardiac function in both young and aging mice, suggesting compensation from other mitochondrial Ub ligases. However, the identities of such additional mitochondrial Ub ligases, as well as their physiological significance in the heart, remain unclear. Here, we demonstrate that Cullin-RING Ub ligase 5 (CRL5) plays a key role in the control of mitochondrial homeostasis in cardiomyocytes. CRL5 belongs to the family of Cullin-RING Ub ligases (CRLs) and consists of the RING box protein RBX2, scaffold protein Cullin 5 (Cul5), and one of 38 substrate receptor proteins. Analysis of the mitochondrial outer membrane-interacting proteome revealed a robust association of CRLs with mitochondria. Pharmacological and genetic perturbations of CRLs inhibited mitochondrial ubiquitination and mitophagy. Subcellular fractionation, live-cell imaging and immunogold electron microscopy further revealed that RBX2 and Cul5, two core components of CRL5, are quickly recruited to mitochondria upon mitochondrial depolarization. Depletion of RBX2 or Cul5 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial function, and increased cell death in cardiomyocytes. Importantly, RBX2 deficiency did not alter Parkin expression, had a more robust inhibitory effect on mitochondrial ubiquitination compared to Parkin deficiency, and remained effective in the absence of Parkin. Moreover, loss of RBX2 attenuated Parkin-mediated ubiquitination, suggesting its dominant, Parkin-independent actions in mitochondria. In vivo , deletion of RBX2 in adult mouse hearts suppressed mitophagic activity and provoked accumulation of damaged mitochondria in myocardium, leading to rapid development of dilated cardiomyopathy and heart failure. Finally, RBX2 was upregulated in pressure overloaded mouse hearts but downregulated in human failing hearts, further supporting its protective role in the heart. Taken together, our data allow us to propose RBX2-CRL5 as a mitochondrial Ub ligase and a physiological regulator of mitochondrial and cardiac integrity.
Abstract GS104: Stress-induced Uhrf1 Epigenetically Modulates Angiogenesis And Cardiac Function In Ventricular Hypertrophy
Authors: Arianna Felicetta, Pierluigi Carullo, Giada Cassanmagnago, Marco Cremonesi, Mauro Passaretti, Federico Colombo, Javier Cibella, Gianluca Basso, Clelia Peano, Gianluigi Condorelli
Journal: Circulation Research (2022)

Heart failure (HF) is accompanied by cardiac hypertrophy (CH) and myocardial tissue remodeling. Epigenetic mechanisms regulate cardiomyocyte (CM) gene expression during CH: the DNA methylation profile and several histone modification marks are profoundly modulated in mouse models of HF and in the human disease. UHRF1 is an epigenetic cofactor connecting DNA methylation to histone methylation. By screening for epigenetic genes upregulated during the early phase of HF, Uhrf1 emerged as a “hit”. We found that UHRF1 is highly expressed in the endothelial cell (EC) compartment under basal conditions in comparison to other myocardial cellular components, and its expression surges in the acute phase of CH induced through transverse aortic constriction (TAC). In vitro studies on HUVECs and H5V cells revealed that silencing of Uhrf1 is associated with defects in cell cycle progression, migration and tube formation. To gain further insight on the role of UHRF1, we generated an EC-specific conditional knockout (cKO) mouse line, Cdh5-CreERT2; Uhrf 1 fl/fl . Compared to control, Uhrf1 -cKO mice subjected to TAC exhibit a worsening of cardiac function associated with increased left ventricular dimension, suggesting a more rapid transition toward HF. Transcriptomic analysis of ECs revealed a robust correlation between UHRF1 depletion and alteration of cell cycle and angiogenesis, in agreement with in vitro results. These results were further corroborated in vivo through EdU injection, matrigel plug and retinal angiogenesis assays, and provided robust evidence for a key role for UHRF1 in the EC response to stress, linking the latter to neo-angiogenesis. We then defined whether the crosstalk between CMs and ECs during stress was altered by the absence of UHRF1. We found that, among other angiocrines, neuregulin-1 (Nrg-1) was strongly downregulated in ECs of Uhrf1 fl/fl mice subjected to TAC. In line with this evidence, ErbB2 and ERK pathways were significantly downregulated in the left ventricle of Uhrf1 fl/fl TAC mice, leading to increased tissue apoptosis.Our study identifies UHRF1 as a critical epigenetic regulator of stress-induced angiogenesis and, more broadly, underlines the relevance of epigenetics in modulating EC gene expression during myocardial stress.
Influence of hypercapnia on rabbit intrapulmonary neuroepithelial bodies: microfluorimetric and morphometric study
Authors: JM Lauweryns, A Tierens, M Decramer
Journal: European Respiratory Journal (1990)

The present investigation was undertaken to investigate the influence of hypercapnia on intrapulmonary neuroepithelial bodies (NEB). Rabbits were mechanically ventilated with a hypercapnic gas mixture (7% carbon dioxide, 20% oxygen, 73% nitrogen). Lung samples were examined by a microspectrographical analysis of the NEB formaldehyde-induced fluorescence to quantify the cytoplasmic 5-hydroxy-tryptamine (5HT) content and by electron microscopy to determine morphometrically the extent of the secretory exocytosis at the basal poles of the NEB epithelial cells. In contrast to our earlier studies on the effects of hypoxia and/or vagal stimulation, hypercapnia did not alter significantly the NEB cytoplasmic fluorescence nor did it affect the corpuscular epithelial exocytosis. NEB appear not to be influenced by hypercapnia to discharge their contents of 5HT and peptides. This investigation appears to support a high selectivity of the intrapulmonary NEB to local hypoxia and changes in vagal efferent output.
Abstract GS106: Asporin, An Extracellular Matrix Protein, Is A Beneficial Regulator Of Cardiac Remodeling
Authors: Deepika Rai, Chengqun Huang, Reetu Thakur, Ankush Sharma, Roberta A Gottlieb, Honit Piplani
Journal: Circulation Research (2022)

Heart failure is accompanied by adverse cardiac remodeling involving extracellular matrix (ECM). Cardiac ECM acts as a major reservoir for many proteins including growth factors, cytokines, collagens, and proteoglycans. Activated fibroblasts during cardiac injury can alter the composition and activity of these ECM proteins. Through unbiased analysis of a microarray dataset of human heart tissue comparing normal hearts (n=135) to hearts with ischemic cardiomyopathy (n=94), we identified Asporin (ASPN) as the top differentially regulated gene (DEG) in ischemic cardiomyopathy; its gene-ontology terms relate closely to fibrosis and cell death. ASPN is a Class I small leucine repeat protein member implicated in cancer, osteoarthritis, and periodontal ligament mineralization. However, its role in cardiac remodeling is still unknown. Here, we initially confirmed our big dataset analysis through cells, mice, and clinical atrial biopsy samples to demonstrate increased ASPN expression after pressure overload or cardiac ischemia/reperfusion injury. We tested the hypothesis that ASPN, being a TGFβ1 inhibitor, can attenuate fibrosis in mouse models of cardiac injury. We found that ASPN is released by cardiac fibroblasts and attenuates TGFβ signaling. Moreover, ASPN -/- mice displayed increased fibrosis and decreased cardiac function after pressure overload by transverse aortic constriction (TAC) in mice. In addition, ASPN protected cardiomyocytes from hypoxia/reoxygenation-induced cell death and regulated autophagy and mitochondrial bioenergetics in cardiomyocytes. Increased infarct size after ischemia/reperfusion injury in ASPN -/- mice confirmed ASPN’s contribution to cardiomyocyte viability. Echocardiography revealed a greater reduction in left ventricular systolic function post-I/R in the ASPN -/- animals compared to wild type. Furthermore, we developed an ASPN-mimic peptide using molecular modeling and docking which when administered to mice prevented TAC-induced fibrosis and preserved heart function. The peptide also reduced infarct size after I/R in mice, demonstrating the translational potential of ASPN-based therapy. Thus, we establish the role of ASPN as a critical ECM molecule that regulates cardiac remodeling to preserve heart function.